1,4-benzodioxane derivatives

ABSTRACT

1,4-Benzodioxane derivatives represented by the following general formula: &lt;CHEM&gt; wherein p stands for an integer of 0 - 2, X and Y are same or different, and each represent a hydrogen atom; or a group represented by the formula -OR in which R denotes a hydrogen atom, a lower alkyl, lower alkoxycarbonyl or acyl group, or a group represented by the formula &lt;CHEM&gt; m being an integer of 1 or 2; cyano group; or carboxy group, n is an integer of 1 - 3, exclusive of the case wherein p = 0 and X = Y = H, or a pharmacologically acceptable salt thereof. Their process for the preparation, pharmacological compositions containing them as active ingredient, their use in the preparation of therapeutic and/or preventive medicament for the treatment of ischemic heart diseases or heart failure and for the control of blood pressure during surgical operations are also described.

This invention relates to 1,4-benzodioxane derivatives having excellenteffects as medicines. More specifically, the present invention isconcerned with 1,4-benzodioxane derivatives represented by the followinggeneral formula (I): ##STR3## wherein p stands for an integer of 0-2, Xand Y are same or different, and each represent a hydrogen atom; or agroup represented by the formula --OR in which R denotes a hydrogenatom, a lower alkyl, lower alkoxycarbonyl or acyl group, or a grouprepresented by the formula ##STR4## m being an integer of 1 or 2; cyanogroup; or carboxy group, n is an integer of 1-3, exclusive of the casewherein p=0 and X=Y=H, or a pharmacologically acceptable salt thereof;their processes for the preparation thereof; and medicines containingsame.

In the above general formula (I), the term "lower alkyl group" as usedin the definition for R means straight-chain or branched alkyl groupshaving 1-6 carbon atoms, for example, alkyl groups such as methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl,tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl and n-hexyl. By the term"lower alkoxy" as used in the term "lower alkoxycarbonyl group", ismeant those derived from the above-described lower alkyl groups.

As illustrative examples of the acyl group, may be mentioned acyl groupsderived from aliphatic monocarboxylic acids having 1-6 carbon atoms suchas formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl,pivaloyl and hexanoyl, acyl groups derived from heterocyclic carboxylicacids such as nicotinoyl group, and so on.

When R means a hydrogen atom, the compounds (I) of this invention may beprovided as their salts including, for example, their alkali metal andalkaline earth metal salts such as their Na, K and Ca salts and theirorganic base salts such as their ethanolamine salts. Needless to say,these salts are embraced in the present invention.

Certain compounds in this invention may also be converted intopharmacologically acceptable salts, for example, their inorganic acidaddition salts such as their hydrochlorides, hydrobromides andhydroiodides and their organic acid addition salts such as theirmaleates, fumarates, succinates, malonates, acetates, citrates andmethanesulfonates.

Nitrite base medicines led by nitroglycerin (hereinafter abbreviatedmerely as "NG") have been used more than 100 years. They are stillconsidered to be effective medicines for angina pectoris even now. Inthe meantime, isosorbide dinitrate (hereinafter abbreviated merely as"ISDN") and the like have been developed to date.

Although the mechanism of effects of such a nitrite base medicine hasnot been fully elucidated, the following theory is considered to be mostcogent. Namely, the nitride base medicine causes veins to expand so thatendovenous pool is allowed to take place. As a result, the intravenousperfusion rate is reduced and the blood pressure in the final stage ofdiastole of the left ventricle is hence reduced. The tension of the leftventricle is therefore reduced, leading to a reduction in theintramyocardinal oxygen consumption.

Under the above-mentioned circumstances, the present inventors haveproceeded for many years with an extensive investigation in order todevelop compounds which are nitro-containing agents different fromconventional NG and ISDN preparation and have stronger activities thanthese conventional medicines. As a result, it has now been found thatcompounds having the below-described structural formula can achieve theabove object.

Namely, the compounds of this invention are 1,4-benzodioxane derivativesrepresented by the following general formula: ##STR5## wherein p standsfor an integer of 0-2, X and Y are same or different, and each representa hydrogen atom; or a group represented by the formula --OR in which Rdenotes a hydrogen atom, a lower alkyl, lower alkoxycarbonyl or acylgroup, or a group represented by the formula ##STR6## m being an integerof 1 or 2; cyano group; or carboxy group, n is an integer of 1-3,exclusive of the case wherein p=0 and X=Y=H, or a pharmacologicallyacceptable salt thereof.

The above-described compounds of this invention have advantageousfeatures such as those described below:

(1) They have strong vasodilative effects on coronary arteries,peripheral arterial vessels and peripheral venous vessels. Thus, inaddition to increasing coronary blood flow, they have advantageousaction of reducing both pre- and post-loads to the heart. In thisregard, their actions are more potent than those of NG and ISDN.

(2) They cause vasodilation at both intravenous and intraduodenaladministration, indicating good absorption from the gastrointestinalsystem.

(3) They have higher LD₅₀ values than NG in mice and hence have widesafety margins. They cause extremely reduced formation of methemoglobinthan NG.

Where R stands for a hydrogen atom in the compounds (I) of thisinvention, it is possible to increase their solubility, for example, byconverting them into sodium salts. Further, nitro-containing compoundstends to adhere to transfusion equipment upon their drip infusion anddevelop trouble frequently. The compounds of this invention are howeverless sticky compared with conventional nitro-containing compounds andare also advantageous in this respect.

The diseases to which the compounds of this invention can be applied asmedicines include heart failure and ischemic heart diseases as typifiedby a variety of angina pectoris (effort angina, angina at rest, variantangina etc.).

They can be also useful for the control of blood pressure duringsurgical operations.

Obejcts of this invention are to provide the novel 1,4-benzodioxanederivatives effective for ischemic heart diseases, heart failure andblood pressure control during an operation, their preparation process,and medicinal compositions which contain these compounds as effectiveingredients for the above-mentioned diseases.

The above and other objects, features and advantages of this inventionwill become apparent from the following description and the appendedclaims, taken in conjunction with the accompanying drawings.

A variety of routes may be contemplated for the preparation of thecompounds of this invention. Of these, certain representative routeswill hereinafter be described specifically in detail.

Preparation Route 1: ##STR7##

Namely, the compound represented by the formula (II) is chosen as astarting material. It is nitrated by a method known per se in the art toprepare the desired product (I). For its nitration, it is reacted in thepresence or absence of a solvent by using a nitrating agent such asacetic anhydride-fuming nitric acid, fuming nitric acid or fuming nitricacid-conc. sulfuric acid. This reaction is usually conducted at about0°-40° C. and as a solvent, acetonitrile, chloroform, dichloromethane,acetic acid or the like is preferred.

By the above reaction, various desired products are formed as a mixturedepending on the degree of nitration (p=0-2). These desired products arethen isolated and purified, for example, by silica gel chromatography orthe like, so that one of the desired product can be obtained.

Where Y is a hydroxyl group bonded to the 8-position, --(CH₂)OH isbonded to the 2-position, X=H and n=1, the starting material, namely,8-hydroxy-2-hydroxymethyl-1,4-benzodioxane represented by the followingstructural formula (III) has already been disclosed, for example, inU.S. Pat. No. 3,101,345. ##STR8## It can be prepared by the processdescribed in the above patent. Namely, it can be obtained by reactingpyrogallol with epichlorohydrin.

A description will next be made particularly of the preparation of8-hydroxy-2-nitratomethyl-7-nitro-1,4-benzodioxane which is arepresentative compound according to the present invention. Itspreparation is shown by the following reaction formula: ##STR9##

Preparation Route 2:

This preparation route is suitable for the preparation of certain1,4-benzodioxane derivatives of the general formula (I) in which Y isrepresented by the formula --OR and R has the same meaning as definedabove.

Although they may also be prepared by Preparation Route 1, it ispossible to obtain them with ease by the following route. ##STR10##

The above reaction is a condensation reaction and can be conducted in ausual manner. Preferable results may generally be obtained if thereaction is carried out in the presence of a base such as pyridine,potassium carbonate or triethylamine while using acetone, DMF or thelike as a solvent.

Certain Pharmacological Experiments will next be given to describe theeffects of the present invention in more detail.

PHARMACOLOGICAL EXPERIMENT 1 Hypotensive effects in spontaneouslyhypertensive rats (SHR) under anesthesia

1. Method

Male SHR of 20 weeks of age or older were anesthetized with sodiumpentobarbital (40 mg/kg, i.p.). The carotid artery and jugular vein werecannulated. Blood pressure was recorded from the carotid artery on apolygraph via a pressure transducer. Test compounds were dissolved in asolution containing 0.9% NaCl and 1% Tween 80 and administered eitherintravenously into the jugular vein or intraduodenally through a cannulainserted into the duodenum.

As a representative of this invention, compound A(8-hydroxy-2-nitrato-methyl-7-nitro-1,4-benzodioxane) was chosen.

2. Results

Results are shown in FIGS. 1 and 2.

FIG. 1 diagrammatically illustrates hypotensive effects in SHR underanesthesia, upon intravenous injection. Values are means ±s.e.m. ( :compound A, ○: NG, : ISDN, Δ: nicorandil). Letter n indicates the numberof animals.

FIG. 2 diagrammatically depicts hypotensive effects in SHR underanesthesia, upon intraduodenal administration. Values are means ±s.e.m.( : compound A, : NG, ○: ISDN, Δ: nicorandil). Letter n indicates thenumber of animals.

Compound A caused a marked hypotension after intravenous administrationat a dose as small as 0.3 μg/kg.

The potency of compound A to cause 30% decrease in means aortic pressurewas 5, 250 and 300 times larger than NG, ISDN and nicorandil(N-[2-(nitroxy)ethyl]-3-pyridinecarboxamide), respectively. Compound Aalso caused a dose-dependent hypotension after intraduodenaladministration. The potency of compound A was about 5, 10 and 30 timeslarger than nicorandil, NG and ISDN, respectively.

PHARMACOLOGICAL EXPERIMENT 2 Effects on the arterial and venous systemsin anesthetized open-chest dogs

1. Methods

Mongrel dogs of either sex, weighing 12-16 kg were subjected toinhalation anesthesia with enflurane under artificial respiration. Thedogs were subjected to thoracotomy through the fourth right intercostalwall and catheters were inserted into the thoracic aorta and rightpulmonary artery. The aortic and pulmonary blood pressures were measuredby means of cathether tip-type piezoelectric transducers.

Test compounds were cumulatively administered with intervals of 30minutes either intravenously or intraduodenally through catheters placedin the left femoral vein and duodenum.

2. Results

The results are summarized in Table 1.

                  TABLE 1                                                         ______________________________________                                                                  Max. change in mean                                                           blood                                                                 Number  pressure at diastole                                           Dose   of      (mm/Hg)                                             Compound Route   (μg/Kg)                                                                             animals                                                                             Aortic Pulmonary                              ______________________________________                                        NG       i.v     3        3     -21.7  -0.8                                            i.v     10       3     -33.3  -3.0                                            i.v     30       3     -40.0  -3.7                                            i.d     30       3     -1.7   -0.7                                            i.d     100      3     -3.3   -1                                              i.d     300      3     -10    -1.7                                   ISDN     i.v     30       3     -2     -2.5                                            i.v     100      3     0      -2.8                                            i.v     300      3     -6     -3.8                                            i.d     30       3     -5     -0.7                                            i.d     100      3     -6.7   -0.7                                            i.d     300      3     -5.8   -1.7                                   Nicorandil                                                                             i.v     30       4     -10.3  -1                                              i.v     100      4     -18.6  -1.5                                            i.v     300      4     -50.9  -2.1                                   Compound A                                                                             i.v     1        3     -23    -2.5                                            i.v     3        3     -39.2  -3.2                                            i.v     10       3     -44.2  -5.3                                            i.d     30       3     -2     -1.5                                            i.d     100      3     -15    -2.5                                            i.d     300      3     -22    -3.5                                   ______________________________________                                    

After intravenous administration, compound A reduced aortic andpulmonary blood pressure dose-dependently. The vasodilating effects ofcompound A on the arterial and venous system as assessed from thereduction in aortic and pulmonary blood pressure respectively, was about3 times more potent than those of nicorandil. The effect of ISDN on theaortic pressure was minimum at a dose-range 30 times larger than that ofcompound A.

Compound A also caused dose-dependent reductions in aortic and pulmonaryblood pressures after intraduodenal administration. The potency ofcompound A was about 3 times larger than that of NG.

Pharmacological Experiment 3 Effects on the coronary blood flow inanesthetized open-chest dogs

1. Methods

Mongrel dogs of either sex weighing 9-14 kg were subjected to inhalationanesthesia with enflurane under artificial respiration. The dogs weresubjected to thoracotomy through the fourth left intercostal wall and amagnetic flow meter prove was attached to the circumflex branch of theleft coronary artery to measure the coronary blood flow. Test compoundswere administered cumulatively at intervals of 10 minutes through acatheter inserted into the left femoral vein.

2. Results

Results are summarized in Table 2.

                  TABLE 2                                                         ______________________________________                                                           Number                                                              Dose      of       Max. increase in coronary                         Compound (μg/Kg)                                                                              animals  blood flow (%)                                    ______________________________________                                        NG       3         3        31.3                                                       10        3        79.7                                                       30        3        165.0                                             Sodium   1         3        0                                                 nitroprusside                                                                          3         3        22.2                                                       10        3        101.9                                             Compound A                                                                             1         3        52.0                                                       3         3        84.7                                                       10        3        127.6                                             ______________________________________                                    

Intravenous administration of compound A caused a marked anddose-dependent increase in coronary blood flow at a dose range as smallas 1-10 μg/kg.

The effect of compound A on the coronary flow was about 3 times morepotent than that of NG.

From the above-described results, it is clear that the compounds of thisinvention have strong vasodilative effects on the coronary andperipheral arteries as well as on the peripheral veins. This means thatthe compounds of this invention are useful as therapeutic compositionsfor ischemic heart diseases such as angina pectoris and cardiacinfarction, and for cardiac failure.

The toxicity of the compounds of this invention will next be described.

Acute toxicity in mice was investigated with respect to8-hydroxy-2-nitratomethyl-7-nitro-1,4-benzodioxane. Its LD₅₀ was 200-250mg/kg at intravenous administration and 500-1,000 mg/kg at oraladministration. A similar experiment was also conducted with anintravenous administration of NG. Its LD₅₀ was 10-15 mg/kg.

From the above results, it is clear that the compounds of this inventionare extremely safer than NG. The present invention has an extremely highvalue for this advantage too.

As apparent from the results of the above-described PharmacologicalExperiments, the compounds of this invention are effective astherapeutic and preventive compositions for ischemic heart diseases,typified by cardiac infarction and a variety of angina pectoris, andheart failure; for the control of blood pressure during a surgicaloperation; etc. They have superior effects compared with conventionalnitro-containing agents and moreover, have higher safety than theconventional nitro-containing agents. Hence, the present invention hasan extremely high value.

When the compounds of this invention are applied for the above-describedobjects, they are administered orally or parenterally (i.e., asinjections or external preparations). Their dose varies depending on thetype and severity of disease and age as well as whether there is anemergency situation or not. No specific limitation is therefore imposedon the dose. The dose may however be on the order of about 0.1-100 mg,preferably 0.5-40 mg, most preferably 1-20 mg per day for an adult. Inthe case of injections, each compound may be administered, for example,at a rate of about 0.1-5 mg/hour, preferably, about 0.5-3 mg/hour byintravenous drip infusion.

In order to form the compounds of this invention into suitable dosageforms, they may be made into such forms as tablets, granules, powders,capsules, injections, external preparations, suppositories, etc. inaccordance with routine techniques employed in this field.

More specifically, for preparing a solid preparation for oraladministration, the active ingredient is mixed with an excipient and, ifnecessary, a binder, disintegrator, lubricant, coloring agent, corrigentand the like, and then formed into tablets, coated tablets, granules,powders, capsules, etc. by methods known per se in the art.

Examples of the excipient may include lactose, corn starch, saccharose,glucose, sorbitol, crystalline cellulose, etc. On the other hand,illustrative binders may include polyvinyl alcohol, polyvinyl ether,ethylcellulose, methylcellulose, gum arabic, tragacanth gum, gelatin,shellac, hydroxypropylcellulose, hydroxypropylstarch, polyvinylpyrrolidone and the like. As illustrative disintegrators, there may bementioned starch, agar, gelatin powder, microcrystalline cellulose,calcium carbonate, sodium hydrogencarbonate, calcium citrate, dextrin,pectin, etc. Lubricants may include magnesium stearate, talc,polyethylene glycol, silica, hardened vegetable oil, etc. by way ofexample. Illustrative coloring agents may include those permitted forincorporation in medicines. As corrigents, use may be made of, forexample, cocoa powder, menthol, aromatic acids, mentha oil, Borneocamphor, cinnamon powder, etc. These tablets and granules may of coursebe applied with sugar or gelatin coating or any other suitable coatingas needed.

For preparing an injection, the active ingredient is added with apH-adjusting agent, buffer, stabilizer, solubilizer, preservative and/orthe like as needed, and then formed into a subcutaneous, intramuscularor intravenous injection by a method known per se in the art.

When a preparation suitable for intravenous drip infusion is desired,the injection may be used as is or alternatively, it may be diluted witha physiological saline or a glucose solution for use in intravenous dripinfusion.

Examples of this invention will next be described. Needless to say, thepresent invention is by no means limited to them.

EXAMPLE 1 ##STR11## (1) Synthesis of8-hydroxy-2-hydroxymethyl-1,4-benzodioxane

Pyrogallol (757 g; 6.0 moles), sodium sulfite (3 g), water (2.2 l) andanhydrous sodium borate (317 g; 1.58 moles) were charged in a 5-l 4-neckflask. The contents were stirred into a solution. After substituting theinterior gas of the flask with argon, there were added with stirring atroom temperature sodium iodide (30 g), sodium hydroxide (120 g; 3.0moles) dissolved in water (300 ml) and epichlorohydrin (610 g; 6.6moles). The resulting mixture was stirred for one day, followed byfurther addition of caustic soda (12 g; 0.3 mole) and epichlorohydrin(167 g; 1.8 moles). The contents were thereafter stirred at roomtemperature for 3 days. The reaction mixture was then washed twice withdichloromethane. While stirring the aqueous layer under ice-cooling, amixture of caustic soda (800 g) and water (1.5 l) was added. Theresulting mixture was then heated back to room temperature, at which itwas stirred for 3 hours.

Concentrated sulfuric acid (1.4 l) was thereafter added the reactionmixture to lower its pH to about 8.0. The reaction mixture was thenextracted three times with ethyl acetate. After washing the ethylacetate layer twice with a saturated aqueous solution of Na₂ B₄ O₇ andthen with a saturated saline, ethyl acetate was distilled off underreduced pressure. The resulting pale yellowish brown oil was subjectedto silica gel chromatography (silica gel: about 2 kg; developer:chloroform-methanol) and then crystallized from chloroform-n-hexane,thereby obtaining 540 g of the title compound, i.e.,8-hydroxy-2-hydroxymethyl-1,4-benzodioxane (yield: about 50%) ascolorless crystals.

Melting point (°C.): 98-102.

(2) Synthesis of 8-hydroxy-2-nitratomethyl-7-nitro-1,4-benzodioxane

8-Hydroxy-2-hydroxymethyl-1,4-benzodioxane (127.4 g; 0.7 mole) obtainedby the procedure (1), urea (1.5 g) and acetonitrile (1 l) were chargedin a 2-l 4-neck flask, to which acetyl nitrate [prepared from 99% fumingnitric acid (134 ml), acetic anhydride (375 g) and concentrated sulfuricacid (several drops) in acetonitrile] was added dropwise with coolingand stirring (internal temperature: about -35° C.). About fifteenminutes later, a solution caustic soda (120 g) dissolved in water (240ml) was carefully added dropwise at temperatures below -30° C.

The reaction mixture was then poured in water (about 3 l). Afterstirring it overnight, the resulting deposit was collected by filtrationand washed first with water and then with methanol. Hot methanol (500ml) was added to the deposit. After stirring and cooling the resultingmixture, the resulting deposit was collected by filtration. Furthermore,hot chloroform (1.5 l) was added to the deposit and the resultingmixture was then filtered under heat to remove insoluble matter. Theinsoluble matter was extracted with hot chloroform (1 l) in the samemanner. The extract was combined with the chloroform solution, followedby an addition of silica gel (about 200 g). After stirring the resultingmixture, it was filtered. Chloroform was then distilled off from thefiltrate, and the residue was dissolved in hot acetone, followed by anaddition of methanol. The deposited crystals were collected byfiltration to obtain 58 g of the title compound, i.e.,8-hydroxy-2-nitratomethyl-7-nitro-1,4-benzodioxane (yield: 30%) asyellowish crystals.

Melting point (°C.): 160-162.

    ______________________________________                                        IR (Nujol ®)cm.sup.-1 :                                                                    1620                                                                                       (ONO.sub.2)                                                      1273                                                         ______________________________________                                    

    ______________________________________                                        Elemental analysis for C.sub.9 H.sub.8 N.sub.2 O.sub.8 :                                 C         H      N                                                 ______________________________________                                        Calculated (%)                                                                             39.71       2.96   10.29                                         Found (%)    39.73       2.88   10.31                                         ______________________________________                                    

EXAMPLE 2 ##STR12##

8-Hydroxy-2-nitratomethyl-7-nitro-1,4-benzodioxane (200 mg) obtained inExample 1 was dissolved in methanol (30 ml), followed by an excessiveaddition of an ether solution of diazomethane at room temperature.Thirty minutes later, the reaction mixture was concentrated underreduced pressure to dryness so that the title compound (220 mg) wasobtained in an oily form. When it was left over in a refrigerator, itwas solidified. Its melting point was 73°-74° C.

    ______________________________________                                        IR (Nujol ®)cm.sup.-1 :                                                                    1625                                                                                       (ONO.sub.2)                                                      1275                                                         ______________________________________                                    

    ______________________________________                                        Elemental analysis for C.sub.10 H.sub.10 N.sub.2 O.sub.8 :                               C         H      N                                                 ______________________________________                                        Calculated (%)                                                                             41.96       3.52   9.79                                          Found (%)    42.13       3.60   9.65                                          ______________________________________                                    

EXAMPLE 3 ##STR13##

8-Hydroxy-2-nitratomethyl-7-nitro-1,4-benzodioxane (200 mg) obtained inExample 1 was dissolved in pyridine (5 ml), followed by an addition ofacetic anhydride. The reaction mixture was heated to 80°-85° C. so as toconduct the intended reaction. The reaction mixture was thenconcentrated under reduced pressure to dryness, followed byrecrystallization from methanol to obtain title compound (200 mg) ascolorless needle-like crystals.

Melting point (°C.): 115-116

    ______________________________________                                         ##STR14##                                                                     ##STR15##                                                                    ______________________________________                                        Elemental analysis for C.sub.11 H.sub.10 N.sub.2 O.sub.9 :                               C         H      N                                                 ______________________________________                                        Calculated (%)                                                                             42.05       3.21   8.92                                          Found (%)    42.22       3.26   8.69                                          ______________________________________                                    

EXAMPLES 4-17

Following the procedures of Examples 1-3, various compounds wereobtained as shown in the following Tables 3 and 4.

                                      TABLE 3                                     __________________________________________________________________________                                                       Elemental analysis                                                            data                       Example                  Appearance       Molecular                                                                              Calculated/found           No.  Compound            m.p. (°C.)                                                                     IR cm.sup.-1                                                                           formula  C (%)                                                                             H                                                                                 N                  __________________________________________________________________________                                                               (%)                 4                                                                                  ##STR16##          Reddish powder 150 - (decomp'd)                                                        ##STR17##                                                                             C.sub.9 H.sub.7 O.sub.8 N.sub.2                                               Na       36.74 36.89                                                                       2.40 2.40                                                                          9.53 9.4           5                                                                                  ##STR18##          Pale yellowish powder 165 (decomp'd)                                                   ##STR19##                                                                             C.sub.15 H.sub.11 O.sub.9                                                     N.sub.3.HCl                                                                            43.55 43.81                                                                       2.92 2.88                                                                         10.16  9.98         6                                                                                  ##STR20##          Pale yellowish crystals 71-73                                                          ##STR21##                                                                             C.sub.12 H.sub.12 O.sub.10                                                    N.sub.2  41.87 41.88                                                                       3.51 3.47                                                                          8.14 8.04          7                                                                                  ##STR22##          Colorless powder  147-149 (decomp'd)                                                   ##STR23##                                                                             C.sub.15 H.sub.19 O.sub.9                                                     N.sub.3.HCl                                                                            42.71 42.83                                                                       4.78 4.88                                                                          9.96 9.78          8                                                                                  ##STR24##          Pale brownish crystals 131-135                                                         ##STR25##                                                                             C.sub.9 H.sub.8 O.sub.8                                                                39.71 39.70                                                                       2.96 2.77                                                                         10.29 10.51         9                                                                                  ##STR26##          Pale yellowish needle-like crystals 78-82                                              ##STR27##                                                                             C.sub.10 H.sub.10 O.sub.8                                                     N.sub.2  41.96 42.18                                                                       3.52 3.29                                                                          9.79 9.76         10                                                                                  ##STR28##          Pale yellowish oil                                                                     ##STR29##                                                                             C.sub.11 H.sub.10 O.sub.9                                                     N.sub.2  42.05 41.89                                                                       3.21 3.08                                                                          8.92 9.03         11                                                                                  ##STR30##          Colorless oil                                                                          ##STR31##                                                                             C.sub.9 H.sub.9 O.sub.6                                                                47.58 47.72                                                                       3.99 3.88                                                                          6.17 6.01         12                                                                                  ##STR32##          Colorless crystals 40-47                                                               ##STR33##                                                                             C.sub.10 H.sub.11 O.sub.6                                                              49.79 49.58                                                                       4.60 4.48                                                                          5.81 5.99         13                                                                                  ##STR34##          Colorless oil                                                                          ##STR35##                                                                             C.sub.9 H.sub.9 O.sub.6                                                                47.58 47.81                                                                       3.99 4.15                                                                          6.17 5.89         14                                                                                  ##STR36##          Colorless oil                                                                          ##STR37##                                                                             C.sub.10 H.sub.11 O.sub.6                                                              49.79 49.91                                                                       4.60 4.46                                                                          5.81 5.66         15                                                                                  ##STR38##          Pale yellowish needle-like crystals 172-173.5                                          ##STR39##                                                                             C.sub.10 H.sub.10 O.sub.8                                                     N.sub.2  41.96 41.87                                                                       3.52 3.52                                                                          9.79 9.80         16                                                                                  ##STR40##          Yellowish prismatic crystals 151-152.5                                                 ##STR41##                                                                             C.sub.9 H.sub.7 O.sub.10                                                      N.sub.3  34.08 33.97                                                                       2.23 2.41                                                                         13.24 13.50        17                                                                                  ##STR42##           Colorless powder 60-62                                                                ##STR43##                                                                             C.sub.9 H.sub.8 O.sub.7                                                                42.19 42.28                                                                       3.15 3.21                                                                         10.94 10.86        __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________    Exam-                     Appearance               Elemental analysis                                                            data                       ple                       m. p.           Molecular                                                                              Calculated/found           No. Compound              (°C.)                                                                         IR cm.sup.-1                                                                           formula  C (%)                                                                             H                                                                                 N                  __________________________________________________________________________                                                               (%)                18                                                                                 ##STR44##            Yellowish crystals 96-98.5                                                            ##STR45##                                                                             C.sub.9 H.sub.8 O.sub.8                                                                39.71 39.86                                                                       2.96 2.90                                                                         10.29 10.31        19                                                                                 ##STR46##            Pale yellowish crystals 67.5-68.5                                                     ##STR47##                                                                             C.sub.12 H.sub.10 O.sub.7                                                     N.sub.2  48.99 48.89                                                                       3.43 3.41                                                                          9.52  9.52        20                                                                                 ##STR48##            Colorless needle-like crystals 111-116 (133-134)                               (Double melting point)                                                               ##STR49##                                                                             C.sub.10 H.sub.8 O.sub.6                                                      N.sub.2  47.62 47.44                                                                       3.20 3.14                                                                         11.11 10.96        21                                                                                 ##STR50##            Yellowish crystals 150-152                                                            ##STR51##                                                                             C.sub.10 H.sub.7 O.sub.8                                                      N.sub.3.1/3H.sub.2 O                                                                   39.60 39.87                                                                       2.53 2.31                                                                         13.86 13.88        22                                                                                 ##STR52##            Yellowish crystals 192-194 (decomp'd)                                                 ##STR53##                                                                             C.sub.10 H.sub.8 O.sub.10                                                     N.sub.2  37.98 38.01                                                                       2.55 2.53                                                                          8.86  8.87        23                                                                                 ##STR54##            Colorless crystals 97.5-98                                                            ##STR55##                                                                             C.sub.11 H.sub.10 O.sub.6                                                     N.sub.2  49.63 49.59                                                                       3.79 3.75                                                                         10.52 10.77        24                                                                                 ##STR56##            Colorless crystals 160-162                                                            ##STR57##                                                                             C.sub.10 H.sub.8 O.sub.6                                                      N.sub.2  47.62 47.81                                                                       3.20 3.17                                                                         11.11 10.65        25                                                                                 ##STR58##            Colorless crystals 132-134                                                            ##STR59##                                                                             C.sub.11 H.sub.11 O.sub.8                                                              46.32 46.44                                                                       3.89 3.78                                                                          4.91  4.77        26                                                                                 ##STR60##            Colorless needle-like crystals 217-218 (decomp'd                              )                                                                                     ##STR61##                                                                             C.sub.10 H.sub.9 O.sub.8                                                               44.29 44.29                                                                       3.35 3.30                                                                          5.17  5.04        27                                                                                 ##STR62##            Colorless oil                                                                         ##STR63##                                                                             C.sub.12 H.sub.13 O.sub.8                                                              48.16 47.87                                                                       4.38 4.26                                                                          4.68              __________________________________________________________________________                                                               4.80           

What is claimed is:
 1. A 1,4-benzodioxane derivative represented by thefollowing formula: ##STR64## wherein p stands for an integer of 0-2, Yrepresents a hydrogen atom; or a group represented by the formula --ORin which R denotes a hydrogen atom, a lower alkyl, lower alkoxycarbonylan alkanoyl, nicotinoyl, or a group represented by the formula ##STR65##in which m is 1 or 2; n is an integer of 1-3, exclusive of the casewherein p=0 and Y=H, or a pharmacologically acceptable salt thereof. 2.The 1,4-benzodioxane derivative or a pharmacologically acceptable saltthereof as claimed in claim 1, wherein n is
 1. 3. The 1,4-benzodioxanederivative or a pharmacologically acceptable salt thereof as claimed inclaim 1, wherein p=n=1.
 4. The 1,4-benzodioxane derivative or apharmacologically acceptable salt thereof as claimed in claim 1, whereinp is
 2. 5. The 1,4-benzodioxane derivative or a pharmacologicallyacceptable salt thereof as claimed in claim 1, wherein Y is a hydroxylgroup.
 6. The 1,4-benzodioxane derivative or a pharmacologicallyacceptable salt thereof as claimed in claim 1, wherein n and pindividually represent 1, Y represents a hydroxyl group, and the nitrogroup is bonded to the 7-position.
 7. A pharmaceutical composition forischemic heart disease, comprising an effective amount for the treatmentof such disease of a 1,4-benzodioxane derivative represented by thefollowing formula: ##STR66## wherein p stands for an integer of 0-2, Yrepresents a hydrogen atom; or a group represented by the formula --ORin which R denotes a hydrogen atom, a lower alkyl, lower alkoxycarbonyl,an alkanoyl, nicotinoyl, or a group represented by the formula ##STR67##in which m is 1 or 2; n is an integer of 1-3, exclusive of the casewherein p=0 and Y=H, or a pharmacologically acceptable salt thereof anda pharmacologically acceptable carrier.
 8. The pharmacologicalcomposition as claimed in claim 7, comprising as an effective ingredienta compound wherein p=1, m=1, and Y=OH, or a pharmacologically acceptablesalt thereof.
 9. The pharmacological composition as claimed in claim 7,comprising, as an effective ingredient,8-hydroxy-2-nitratomethyl-7-nitro-1,4-benzodioxane or apharmacologically acceptable salt thereof.
 10. A method for thetreatment of ischemic heart disease which comprises administering to apatient suffering from the said disease a therapeutically effectiveamount of a 1,4-benzodioxane derivative represented by the followingformula: ##STR68## wherein p represents an integer of 0 to 2, Yrepresents hydrogen atom; or a group represented by the formula --OR inwhich R denotes hydrogen atom, a lower alkyl, lower alkoxycarbonyl, analkanoyl, nicotinoyl, or a group represented by the formula ##STR69## inwhich m is 1 or 2; n is an integer of 1 to 3, exclusive of the casewherein p=0 and Y=H, or a pharmacologically acceptable salt thereof.